The present invention relates to devices and methods for stirring (intermixing) at least one liquid, i.e. one or more liquids, and in particular to devices and methods for stirring one or more liquids in a centrifugal system while using centrifugal forces, for example in the field of centrifugal microfluidics.
Centrifugal microfluidics is applied mainly in the field of life sciences, in particular in laboratory analytics. It serves to automate process flows while replacing operations such as pipetting, mixing, measuring, aliquoting and centrifuging. The basic operation of mixing here plays a central part in numerous biochemical applications.
Due to a centrifugal force acting in a radially outward manner, mixtures of liquids and/or of liquids and particles comprising segments of different densities are separated, rather than mixed, on a centrifugal platform. In order to bypass this separating force while nevertheless performing mixing, there are technical solutions that either create a sufficiently convective mixture due to rapid changes in centrifugal acceleration, or that achieve intermixing by means of a counterforce, e.g. a spring or pneumatics, by means of pumping in a reciprocating manner. Here, appropriate geometric structures as obstacles may decisively improve intermixture.
Centrifugal microfluidic platforms were mixing operations are realized by changing the rotational frequency are described in [4] and [5]; in known realizations for mixing on centrifugal platforms, mixing is realized in a purely diffusive manner or by the change in centrifugal acceleration. Stirring may be effected by filling and emptying a compression chamber, as is described in [4], or may be effected directly on account of inertial forces accompanying changes in acceleration, as is described in [5]. A further example of mixing on the centrifugal platform is a Coriolis mixer in accordance with [6]. Here, liquid is transported from a radially inner position to a radially outer position. Intermixture is effected by means of Coriolis forces.
[7] shows a device for mixing in a rotating system, wherein a gas bubble is reciprocated within an ampule. When the centrifuge comes to a halt, the gas bubble moves upward. Due to a specific arrangement of the ampule within the centrifuge, the gas bubble simultaneously moves radially outward. During rotation, the centrifugal force is predominant, and the gas bubble will again move radially inward due to the buoyancy within the liquid. By accelerating and decelerating the centrifuge, the gas bubble is reciprocated, and the liquid is stirred by the movement of the gas bubble. A non-rotating system wherein centrifugal forces are created via a rotating liquid flow is shown in [8]. The gas is added from outside under pressure, stirs the liquid, and is extracted again internally.
Mixing on a centrifugal platform that is realized by the change in centrifugal acceleration is also described in [9]; what is shown is stirring by filling and emptying a compression chamber. In a further example, a mixing pond or a deflectable liquid-tight membrane is periodically filled with liquid and emptied by changes in centrifugal acceleration, see [10]. Due to an obstacle being circumflowed, intermixing is reinforced. Stirring on account of inertial forces accompanying changes in acceleration is demonstrated in [11].
Outside of centrifugal systems, gas bubble reactors are known. Gas bubble reactors are a widely employed method in chemical, biochemical, pharmaceutical, and petrochemical industries. This is due to excellent masses and heat transfer properties with very good mixing properties, as is described in [1].
In microfluidics, gas bubbles within small channels are also used for mixing, as is described in [2]. Here, gas bubbles are located within small channels. Due to surface forces of the gas bubbles, flow profiles are disturbed, and stirring is induced. In addition, application of miniaturized bubble reactors for cultivating cells has been demonstrated in [3]. Here, a gas is introduced into a small reactor so as to provide the cells with nutrients.
Finally, a method of performing radially inward pumping wherein gas is introduced into a system from outside is known from [12].